Deep brain stimulation (DBS) is an effective, relatively safe, reversible, and adjustable treatment modality for medically-refractory movement disorders. It has had little application in persons with spinal cord injury (SCI), even though a significant percentage of new and chronic injuries are classified as motor incomplete and have spared connections. Recent work in our laboratory has pointed to a potential target for locomotor control after partial SCI. This is the mesencephalic locomotor region or MLR, a major coordinating center for activation of both locomotor command and descending modulatory pathways. Based on our studies, DBS of the MLR (mlrDBS) enhances neurotransmission along descending pathways innervating locomotor-generating neurons of the spinal cord. Furthermore, mlrDBS produces immediate and highly significant improvements in gait, locomotor speed and endurance in animals with mild and clinically relevant mid-thoracic contusion (moderate and severe) injuries. To achieve maximal clinical benefit from DBS and to minimize potential adverse effects, DBS electrodes need to be placed precisely into the target structure and the stimulation parameters must be optimized. This is especially important for its use after SCI since pathways responsible for generating locomotion are compromised and clinical benefit will depend upon utilizing the surviving pathways to the fullest extent possible. Unfortunately, there is great controversy concerning the anatomical location of the optimal site for mlrDBS in humans, indicating the importance of large animal testing to minimize the probability of negative or suboptimal clinical results, collateral damage to structures surrounding the MLR, as well as unwanted clinical side effects from stimulation. As part of our long-term goal of developing and optimizing treatments for SCI paralysis, the overall objective of this application is to determine the therapeutic potential of mlrDBS to improve walking following anatomically incomplete, acute and chronic SCI in a large animal model. We hypothesize that locomotion may be facilitated in either acute or chronic stages of injury. We shall pursue the following specific aims: In Aim 1, we propose to first identify and characterize the MLR in uninjured animals, establishing optimal stimulation sites and parameters of stimulation for controlling locomotor responses. In Aim 2, we will assess the ability of mlrDBS to enhance locomotor performance following acute and chronic incomplete thoracic SCI once optimal location and stimulation parameters have been established. The study will provide testing of this novel application of DBS in a large animal preclinical setting, to establish efficacy and to delimi the potential benefits of this procedure as a rehabilitation strategy for differing grades of injur. We expect this work to lead to a Phase 1 clinical study and establish a baseline for future work concerning combinatorial strategies utilizing supplementary transmitter replacement in combination with locomotor training and functional electrical stimulation.